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Type 1 Diabetes Mellitus – In the Quest for an Oral Agent, Do Sodium-Glucose Cotransporter Inhibitors Summon the

FURY or Leave Us TOOTHLESS?

Cameron Stuart Pickard, Pharm.D. PGY2 Ambulatory Care Pharmacy Resident

South Texas Veterans Health Care System, San Antonio, Texas The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center University of Texas Health San Antonio

September 28th, 2018

Learning Objectives: 1. Provide a basic overview of type 1 diabetes mellitus.2. Discuss the significance of diabetic ketoacidosis.3. Evaluate the literature pertaining to the utilization of sodium-glucose cotransporter inhibitors in

the treatment of type 1 diabetes mellitus.4. Recommend optimal pharmacotherapeutic regimen in an adult patient with type 1 diabetes

mellitus given patient specific factors.

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Type 1 Diabetes Mellitus (T1DM) 1. Definition: absolute insulin deficiency most commonly due to autoimmune β-cell destruction1,2 2. Epidemiology

A. 20173 i. 1.1 million individuals younger than 20 years (yrs) of age with T1DM globally ii. 216,300 North America and Caribbean; 169,900 United States (U.S.)

B. 20154,5 i. 29 million adults worldwide with T1DM ii. Global incidence of T1DM increasing by approximately 3% annually iii. Roughly 1.5 million estimated to have T1DM in U.S.

C. Risk i. Overall lifetime risk 1/250 people6 ii. Increases with the number of relevant autoantibodies detected iii. Rate of progression to T1DM after autoantibody seroconversion7

1. ≥ 2 autoantibodies (585 children): 5-year (yr) follow up: 43.5%, 10-yr follow up: 69.7%, and 15-yr follow up: 84.2%

2. 1 autoantibody (474 children): 10-yr follow up: 14.5% iv. Geographic variability in annual incidence6,8

1. 0.73/100,000 in China, 23/100,000 in U.S., and 60/100,000 in Finland 2. Evidence that migrants from low incidence country soon develop higher rate

incidence of new country of residence v. Age and gender: incidence peaks at ages of 2, 4-6, and 10-14 yrs, with a slightly

higher prevalence in males8,9 D. Fewer than 33% of adults with T1DM achieve hemoglobin A1c (HbA1c) < 7.0% and most are

overweight or obese10-12 3. Etiology

A. Immune-mediated1,8,13 i. Previously referred to as insulin-dependent diabetes or juvenile-onset diabetes ii. 5-10% of diabetic population iii. Recent evidence suggests adult onset occurs in up to 50% of cases14 iv. Non-obesity-related v. Genetically susceptible and exposed to poorly defined environmental trigger

1. Presence of ≥ 1 autoimmune markers a. Islet-cell antibodies (ICA) – most common b. Antibodies present in 90% of individuals at time of diagnosis6

2. Human leukocyte antigen (HLA)-DQA and DQB genes predispose or protect depending on HLA-DR/DQ allele

3. 60 non-HLA loci also associated with risk of developing T1DM vi. Increased risk of developing additional autoimmune disorders2,15

B. Idiopathic: no evidence of β-cell autoimmunity13 4. Pathophysiology

A. General overview i. Preclinical period2

1. Positive autoimmune markers 2. β-cell destruction mediated by macrophages and T lymphocytes 3. Remit or progress to β-cell failure

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ii. T1DM: hyperglycemia resulting from 80-90% of β-cell population eradication2 iii. Potential for honeymoon period2,8

1. Transient fall in insulin requirement shortly after clinical onset of T1DM as β-cell function improves

2. Significant and longer remission associated with older age of T1DM onset, less severe initial presentation, and absent to low levels of ICA or tyrosine phosphatase-like protein insulinoma antigen-2

iv. Total β-cell failure B. Immunopathogenesis6

i. Presentation of β-cell peptides by antigen-presenting cells migrate to pancreatic lymph nodes and interact with CD4+ T lymphocytes

ii. CD4+ T lymphocytes activate CD8+ T cells lyse β-cells expressing antigen via major histocompatibility complex class 1 surface molecule

iii. Innate immune cells release proinflammatory cytokines and reactive oxygen species causing further β-cell destruction

iv. Defects in regulatory T lymphocytes fail to suppress autoimmunity v. Activated T cells in pancreatic lymph node stimulate B lymphocytes to produce

autoantibodies C. Rate of progression dependent on antibody: age of detection, number, titer, and specificity1

5. Symptoms3

Figure 1 – Symptoms in T1DM

6. Complications A. Acute: hypoglycemia, diabetic ketoacidosis (DKA), and infection B. Chronic

i. Macrovascular: cardiovascular (CV) (leading cause of death in T1DM of long duration), cerebrovascular, and peripheral vascular disease

ii. Microvascular: retinopathy (leading cause of blindness), neuropathy, and nephropathy (leading cause of end-stage renal disease (ESRD))8

C. Landmark trial and long-term follow-up study Table 1: Effect of Intensive Glycemic Control on Complication Development and Progression

Trial Results

Diabetes Control and Complications Trial – 199316

• Strict glycemic control in T1DM delays onset and slows progression of microvascular complications

• Severe hypoglycemia (SH) approximately 3x higher in intensive-therapy group (62/100 patient(pt)-yrs vs. 19/100 pt-yrs; P<0.001)

• DKA event rates 2.0/100 pt-yrs intensive-therapy group vs. 1.8/100 pt-yrs conventional therapy group

Epidemiology of Diabetes Interventions and Complications study – 200517

• Period of strict glycemic control reduced risk of first CV event by 42% (P = 0.02) and risk of nonfatal myocardial infarction (MI), stroke, or death from cardiovascular disease (CVD) by 57%

7. Screening and diagnosis A. Screening with autoantibody panel only recommended in setting of research trial or first-

degree family members of proband with T1DM due to lack of approved therapeutic interventions in general1

Abnormal thirst and dry

mouth

Sudden weight loss

Frequent urination

Lack of energy and fatigue

Constant hunger Blurred vision

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B. Three distinct stages Table 2: American Diabetes Association (ADA) Staging Based on Degree of Dysglycemia and Symptoms1

Stage 1 2 3

Characteristics Autoimmunity

Normoglycemia Presymptomatic

Autoimmunity Dysglycemia

Presymptomatic

New-onset hyperglycemia Symptomatic

Diagnostic criteria

Multiple autoantibodies

No impaired glucose tolerance (IGT) or impaired

fasting glucose (IFG)

Multiple autoantibodies Dysglycemia: IFG and/or IGT

Fasting plasma glucose (FPG) 100-125 mg/dL 2-hour (hr) plasma glucose (PG) 140-199

mg/dL

HbA1c 5.7-6.4% or ≥ 10% increase in A1c

Clinical symptoms

Diabetes by standard criteria

C. C-peptide, measure of insulin secretion, negligible and useful if type of diabetes in question D. Diagnostic criteria1

Table 3: Diagnosis Criteria in Nonpregnant Patients (pts) Fasting blood glucose (FBG) ≥ 126 mg/dL OR Without explicit hyperglycemia,

confirm with repeat testing

*Dysglycemia potentially rapid in T1DM, and thus, HbA1c less sensitive

2-hr PG ≥ 200 mg/dL during oral glucose tolerance test OR HbA1c ≥ 6.5%* OR Classic symptoms of hyperglycemia/hyperglycemic crisis with random PG ≥ 200 mg/dL

8. Management A. Monitoring18-20

i. Glycemic goals 1. HbA1c

2. ADA capillary point-of-care testing, continuous glucose monitoring (CGM), and laboratory measurement

a. Nonpregnant adults i. Preprandial PG: 80-130 mg/dL ii. Peak postprandial PG: < 180 mg/dL

b. Pregnant adults i. Fasting: < 95 mg/dL ii. 1-hr postprandial: < 140 mg/dL iii. 2-hr postprandial: < 120 mg/dL

c. Children/adolescents i. Preprandial PG: 90-130 mg/dL ii. Bedtime/overnight: 90-150 mg/dL

ii. Management of CV risk factors: blood pressure and lipid control iii. Microvascular complications

B. Lifestyle management21,22 i. Diabetes self-management education and support

Table 4: ADA HbA1c Goals Groups General Recommendation Nonpregnant adults < 7.0% Pregnant adults 6.0-6.5% Children/adolescents < 7.5%

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ii. Medical nutrition therapy iii. Physical activity iv. Smoking cessation counseling v. Psychosocial care

C. Pharmacotherapy22,23 i. No Food and Drug Administration (FDA)-approved oral agents

1. Metformin a. May reduce insulin requirement and improve metabolic control b. Does not improve glycemic control24 c. CV benefit remains under investigation

2. Dipeptidyl peptidase 4 inhibitors: area of current study along with glucagon-like peptide 1 receptor agonists due to potential β-cell preservation and reduction in glucagon secretion

ii. Amylin analog: pramlintide 1. Mechanism of action (MoA): helps control postprandial glucose excursions

by slowing gastric emptying, enhancing satiety, and reducing glucagon secretion

2. Dosing: 15 mcg subcutaneously immediately prior to main meals titrated in 15-mcg increments, as tolerated, to a max dose of 60 mcg with each meal

a. Titrate no more frequently than every 3 days b. Reduce preprandial insulin dose (including combination

preparations) by 50% to avoid hypoglycemia 3. Adverse effects (AEs)

a. Boxed warning for SH, so avoid if hypoglycemia unawareness or frequent hypoglycemia

b. Nausea, abdominal pain, vomiting, anorexia, and headache iii. Insulin

1. MoA: facilitates uptake of glucose by skeletal muscle and fat, inhibits hepatic glucose production, and suppresses free fatty acid release from adipocytes

2. Modes of administration a. Multiple daily injections (MDI)

i. Basal to control FBG and prevent ketosis ii. Bolus to control postprandial hyperglycemia

b. Continuous subcutaneous insulin infusion (CSII) i. Pump utilizes rapid-acting insulins or U-500 to allow pt-

specific hourly basal and bolus dosing ii. Pt education and carbohydrate counting essential iii. Approximately 64% of U.S. pts use insulin pump25

3. AEs: hypoglycemia, weight gain, and injection-site reactions 4. Honeymoon phase caution

D. Surgical22,23 i. Pancreas and islet transplantation – require life-long immunosuppression ii. Reserve modalities for those

1. Undergoing simultaneous or following renal transplantation 2. Recurrent ketoacidosis or SH

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Acute Life-Threatening Complications

1. Hypoglycemia

A. Definition18 i. Hypoglycemia alert value: PG ≤ 70 mg/dL ii. Clinically significant hypoglycemia: PG < 54 mg/dL iii. SH: severe cognitive impairment requiring treatment assistance

B. Epidemiology i. 4-10% of T1DM-related deaths26-28 ii. SH6,8

1. Improvements in glucose monitoring and insulin now reveal similar rates between intensive and non-intensive glycemic control

2. 26% experience episode within 4 yrs of diagnosis 3. 11.8% of 7012 U.S. adults with ≥ 1 event in past 12 months (mos)29

a. HbA1c i. Lowest: 8.3% with A1c 7.0-7.5% ii. Highest: 13.9% with A1c < 6.5%, 13.7% with A1c 8.0-< 9.0%

b. Duration of diabetes i. Lowest: 8.6% with duration < 20 yrs ii. Highest: 18.6% with duration ≥ 40 yrs

c. Higher frequency associated with lower socioeconomic status C. Signs and symptoms: sweating, anxiety, nausea, headache, tachycardia, hunger, shakiness,

blurred vision, dizziness, irritability, confusion, weakness, fatigue, and paleness18,22 D. Treatment18,22

i. If hypoglycemia alert value: 1. Ingest 15-20 g of glucose or equivalent 2. Repeat if blood glucose (BG) remains < 70 mg/dL after 15 minutes 3. Ingest snack or meal after glucose normalized

ii. Clinically significant hypoglycemia with altered consciousness: utilize glucagon 1 mg intramuscularly and/or intravenous dextrose, and ease glucose targets

2. DKA A. Definition: metabolic decompensation characterized by hyperglycemia, ketonemia, and

metabolic acidosis30 B. Epidemiology

i. Initial presentation 1. Initial manifestation of diabetes in 27-37% of pts 1,31,32 2. More common with disadvantaged socioeconomic background2

ii. Incidence 1. Overall: 8/100 person-yrs and increases with age in girls, high reported

insulin dose, higher HbA1c, and older children with limited access to care secondary to underinsurance or presence of psychiatric disorders8

2. Hospital admissions in U.S.30 a. > 130,000/yr, with majority of cases recurrent b. 30% increase between 1995 to 2005

3. Age group a. More common overall number of events in adults30

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b. Frequency in U.S. from T1D Exchange registry of > 30,000 pts25

Figure 2 – U.S. Frequency by Age Group

4. Percentage of 7012 U.S. adults with ≥ 1 event in past 12 mos: female (5.5%) vs. male (4.0%)29

5. 2.3% with CSII and 4.3% with MDI10 iii. Mortality

1. 1-5% of DKA episodes30,33,34 a. < 1% in adults, > 5% in elderly or those with life-threatening illnesses b. Death usually attributed to precipitating factor/illness

2. Accounts for 13-19% of T1DM-related deaths26,27,35 3. By age group: Danish Cause of Death Registry: 1996 to 2000 revealed 55

deaths secondary to DKA in pts with T1DM36

Figure 3 – Deaths by Age Group

iv. Cost: $2.4 billion dollars/yr for treatment30 C. Precipitating factors30,37

i. Discontinuation or inadequate insulin ii. Physiologic stressors (e.g., cerebrovascular accident (CVA), MI, and pancreatitis) iii. Infections (30-50% cases worldwide) iv. Other drugs (e.g., corticosteroids, thiazides, olanzapine, risperidone, and cocaine)

D. Pathophysiology30,37 i. Absolute or relative insulin deficiency stimulates elevation of counterregulatory

hormones (glucagon, catecholamines, cortisol, and growth hormone) ii. Inability to utilize glucose results in:

1. Increased lipolysis that releases fatty acids and glycerol a. Free fatty acids precursor to ketoacids in the liver b. Glycerol substrate for gluconeogenesis in liver and kidney

2. Increased proteolysis and glycogenolysis to produce glucose iii. Hyperglycemia promotes osmotic diuresis causing dehydration, metabolic acidosis,

and hyperosmolar state E. Signs and symptoms: polyuria, polydipsia, polyphagia, weight loss, fatigue, dyspnea, vomiting,

preceding febrile illness, abdominal pain, dehydration, tachycardia, poor skin turgor, dry

4%6%

4%5% 5%

2%1%

2%

0%2%4%6%8%

10%

Overall < 6 6-12 13-17 18-25 26-49 50-64 > 64

Freq

uenc

y

Age (yrs)

Frequency of DKA in U.S. During 2015

< 30 y.o.9.1%

(5 of 55)

30-50 y.o.18.2%

(10 of 55)

51-70 y.o.34.5%

(19 of 55)

> 70 y.o.38.2%

(21 of 55)

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mucous membranes, orthostatic hypotension, Kussmaul respirations, fruity breath, somnolence, lethargy, coma, hyponatremia, and hyperkalemia30,37

F. Diagnostic criteria33 Table 5: DKA Diagnostic Criteria

Severity Mild Moderate Severe PG (mg/dL) > 250 > 250 > 250 Arterial pH 7.25-7.30 7.00-7.24 < 7.0 Serum bicarbonate (mEq/L) 15-18 10-14 < 10 Urine ketone Positive Positive Positive Serum ketone Positive Positive Positive Effective serum osmolality Variable Variable Variable Anion gap > 10 > 12 > 12 Mental status Alert Alert/drowsy Stupor/coma

G. Treatment30,37 i. Underlying cause, fluid replacement, and insulin essential ii. May require administration of potassium, bicarbonate, phosphate, and magnesium

H. Complications: cerebral edema, hypoglycemia, hypokalemia, acute renal failure, and shock37 I. Prevention strategies30,37

i. Diabetes education programs, and improved follow-up and access to care ii. Access to supplies (e.g., glucose and ketone monitoring) and prescriptions (e.g., basal

insulin prescription in case pump fails) iii. Sick-day management education

Sodium-Glucose Cotransporter (SGLT) Inhibitors 1. SGLT2 inhibitors

Table 6: SGLT2 Inhibitors

Agent Canagliflozin (Invokana®)38

Dapagliflozin (Farxiga®)39

Empagliflozin (Jardiance®)40

Ertugliflozin (Steglatro®)41

MoA Inhibit SGLT2 in proximal convoluted tubules, thereby reducing reabsorption of filtered glucose and lowering renal threshold for glucose, leading to increased

glucose excretion in urine

FDA indication Type 2 diabetes mellitus (T2DM) T2DM

T2DM

Risk reduction of CV mortality in adults with

T2DM and CVD

T2DM

FDA approval March 2013 January 2014 August 2014 December 2017

Boxed warning Lower limb amputations in T2DM pts with CVD or at

risk for CVD - - -

Contraindications

Hypersensitivity

Severe renal impairment (estimated glomerular

Hypersensitivity

Severe renal impairment,

ESRD, dialysis

Hypersensitivity

Severe renal impairment,

ESRD, dialysis

Hypersensitivity

Severe renal impairment,

ESRD, dialysis

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filtration rate (eGFR) < 30 mL/min/1.73 m2), or ESRD

Dose 100 mg once daily; may increase to 300 mg once

daily

5 mg once daily; may

increase to 10 mg once daily

10 mg once daily; may

increase to 25 mg once daily

5 mg once daily; may

increase to 15 mg once daily

Dosing in renal impairment

If eGFR 45-59 mL/min/1.73 m2, 100 mg daily max dose

If eGFR < 45 mL/min/1.73 m2, discontinue or do not

initiate

If eGFR < 60 mL/min/1.73

m2, discontinue or do not

initiate

If eGFR < 45 mL/min/1.73

m2, discontinue or do not

initiate

If eGFR < 60 mL/min/1.73

m2, discontinue or do not

initiate

Pediatric dosing Safety and efficacy not established in pediatric pts

Administration Prior to first meal of day Morning with or without food

Morning with or without food

Morning with or without food

AEs Common: urinary tract infection (UTI) and genital mycotic infection (GMI)

Serious: hypotension, DKA (including euglycemic), hypoglycemia, hypersensitivity, bone fracture, kidney injury/renal impairment, and urosepsis

A. FDA Drug Safety Communication i. May 201542

1. SGLT2 inhibitor use may lead to ketoacidosis 2. FDA Adverse Event Reporting System (FAERS) database: March 2013 to June

2014 revealed 20 cases of acidosis (DKA, ketoacidosis, or ketosis) 3. Cases mostly T2DM pts with only slightly elevated blood sugar levels

ii. December 201543 1. FDA revised SGLT2 inhibitor labels with warning for ketoacidosis 2. FAERS database: extended to May 2015 and reported 73 cases ketoacidosis 3. Many cases not immediately recognized as BG levels below 250 mg/dL (i.e.,

euglycemic DKA) 4. Required manufacturers conduct analysis of spontaneous postmarketing

reports of ketoacidosis with follow-up for period of 5 yrs B. Landmark trials in T2DM

i. EMPA-REG Outcome: significant reduction in major adverse CV events and renal outcomes demonstrated44,45

ii. CANVAS and CANVAS-R: significant reduction in major adverse CV events, potential renoprotection, and increased risk of amputation46

2. SGLT1/SGLT2 inhibitor – sotagliflozin (Zynquista™) A. Investigational dual inhibitor of SGLT1 and SGLT2 B. MoA47-49

i. SGLT2 inhibition ii. SGLT1 inhibition

1. Reduces glucose and galactose absorption in proximal intestine and augments release of gastrointestinal incretins, serving to blunt and delay postprandial hyperglycemia

2. Not thought to have meaningful renal SGLT1 inhibition50 C. AEs: nausea, bloating, diarrhea, DKA, genitourinary infections, and hypoglycemia49-51 D. Sanofi submitted New Drug Application to FDA March 2018 for use in T1DM

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E. May 2018, FDA accepted regulatory filing with a March 2019 targeted FDA action date Clinical Controversy: SGLT Inhibitors, a Viable Option in T1DM? Background Literature Review

Table 7: Background Literature Author Findings

Mudaliar et al.52 Nov 2012

• First trial to explore administration of SGLT2 inhibitor – remogliflozin in T1DM • Ten individuals on CSII provided 5 randomized treatments including placebo (PBO), prandial

insulin, 50 mg remogliflozin, 150 mg remogliflozin, and 500 mg remogliflozin as single doses at different treatment periods

• Remogliflozin reduced mean glucose concentrations relative to PBO without AEs Perkins et al.53 May 2014

• 40 MDI/CSII pts completed 8 weeks (wks) of empagliflozin 25 mg daily • Significantly decreased HbA1c, fasting glucose, daily insulin use, symptomatic hypoglycemia,

weight, and waist circumference • Two pts withdrawn secondary to DKA episodes within 3 days of initiation

Henry et al.54 Mar 2015

• 70 MDI/CSII adults randomized to dapagliflozin 1 mg, 2.5 mg, 5 mg (D5), 10 mg (D10), or PBO once daily for 2 wks to assess short-term safety

• Hypoglycemia common across all treatments (60.0-92.3%) with no dose relation • One major hypoglycemic event requiring assistance among dapagliflozin groups related to

not reducing insulin dose as investigator instructed, and no episodes of DKA Sands et al.48 July 2015

• 33 MDI/CSII adults randomized to daily sotagliflozin 400 mg (S400) or PBO for 29 days • Sotagliflozin significantly decreased HbA1c, total daily insulin dose (TDD), bolus insulin dose,

mean daily glucose, percentage of time in hyperglycemic range, and body weight • No severe hypoglycemic events • Two episodes of DKA in sotagliflozin group; deemed pump-related

Pieber et al.55 Oct 2015

• Empagliflozin as Adjunctive to inSulin thErapy (EASE)-1 trial, 75 pts on MDI randomized to receive daily empagliflozin 2.5 mg, 10 mg, 25 mg, or PBO as insulin adjunct for 28 days

• Empagliflozin significantly decreased HbA1c, TDD, and weight without episode of DKA or SH

Randomized Controlled Trials (RCTs)

Henry RR, Thakkar P, Tong C, Polidori D, Alba M. Efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diabetes Care.

2015;38(12):2258-2265.56 Objective Evaluate canagliflozin as an adjunct to insulin to achieve adequate glycemic control in

adults with T1DM Study Design Phase 2, multicenter, randomized, double-blind, PBO-controlled trial

• May 2014 to June 2015 at multiple sites across U.S. and Canada • Randomized 1:1:1 to once daily canagliflozin 100 mg (C100), canagliflozin 300 mg

(C300), or PBO prior to first meal of day for 18 wks; stratified by use of CSII vs. MDI • 2 wks of safety follow-up after 18-week (wk) treatment period • If HbA1c ≤ 8.0%, recommended basal reduced 20%; if > 8.0%, recommended basal

reduced 10% prior to randomization

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• Lab HbA1c and FPG masked after randomization • Algorithms provided for pts to titrate basal insulin to achieve FBG of 80 to < 120

mg/dL and bolus insulin to achieve pre-lunch, pre-dinner, and bedtime glucose of 80 to < 120 mg/dL; investigators could also recommend adjustments

Population Inclusion: • Adults 25-65 yrs of age

with T1DM for ≥ 1 yr • Fasting C-peptide of < 0.6

ng/mL at screening • HbA1c 7.0-9.0% • Body mass index (BMI)

21-35 kg/m2 • Stable insulin regimen

and method of administration for ≥ 8 wks prior to screening

Exclusion: • History (hx) of T2DM, pancreas or β-cell

transplantation, or diabetes due to pancreatitis or pancreatectomy

• SH or DKA event within 6 mos of start • MI, unstable angina, revascularization, or CVA ≤ 12

wks prior to screening • New York Heart Association (NYHA) class III-IV • Uncontrolled hypertension • eGFR < 70 mL/min/1.73 mL2; if fell below 60 during

study, dismissed from trial • Antihyperglycemic agent other than insulin within 12

wks of screening Outcome(s) Primary: proportion of adults with HbA1c reduction ≥ 0.4% and no weight increase;

sensitivity analysis with HbA1c reduction ≥ 0.4% and < 1 kg change in weight Secondary: change in baseline in HbA1c, FPG, weight, and basal/bolus dose requirements, proportion of adults with HbA1c < 7.0%, and incidence of documented hypoglycemia (including SH) and symptomatic hypoglycemia Safety: adverse events including ketone-related events

Statistical Methods

• Modified intent-to-treat (mITT) with pts randomized who received ≥ 1 dose • Assumed 40% of C100 and C300 groups, along with 20% of PBO group, would meet

primary endpoint to determine sample size of 100 pts/group to provide ~80% power to compare each dose with PBO; planned 110 pts/group

• 2-sided α of 0.05 for primary efficacy endpoint • Primary efficacy endpoint analyzed with generalized linear mixed model • Statistical comparisons between canagliflozin and PBO only performed for primary

endpoint (P values); 95% confidence interval (CI) provided for non-prespecified endpoints for descriptive purposes

Baseline Characteristics

• 614 enrolled 352 randomized 351 administered ≥ 1 dose: PBO (n = 117), C100 (n = 117), C300 (n = 117): 328 (93.4%) completed 18-wks

• C100 higher % male (59.0 vs. C300 55.6 vs. PBO 53.8) and white (94.9 vs. C300 87.2 vs. PBO 90.6), but lower % prior SH (12.8 vs. C300 16.2 vs. PBO 15.4)

• TDD baseline: 57.8 units/day PBO vs. 52.0 units/day C100 vs. 52.4 units/day C300 • Average (avg) age 42.3 yrs, BMI 28.1 kg/m2, duration of T1DM 22.4 yrs, HbA1c 7.9%,

and eGFR 96.4 mL/min/1.73 m2 • CSII 62.4% (61.5% PBO vs. 63.2% C100 vs. 62.4% C300) • Hx of SH episode 14.8% and DKA event 12.0%

Endpoints Primary: • Larger proportion of adults had HbA1c decrease ≥ 0.4% and no weight increase with

canagliflozin: PBO 14.5%, C100 36.9%, C300 41.4%; P < 0.001 for both comparisons o HbA1c decrease ≥ 0.4%: PBO 22.7%, C100 45.0%, C300 43.2% o No weight increase: PBO 49.1%, C100 83.8%, C300 96.4%

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• Sensitivity analysis: proportion of participants with HbA1c reduction ≥ 0.4% and weight change < 1.0 kg: PBO 17.3%, C100 39.6%, C300 43.2%

Secondary: Secondary Efficacy Outcomes

Endpoint

C100 vs. PBO C300 vs. PBO LS Mean

Difference from PBO

95% CI LS Mean

Difference from PBO

95% CI

HbA1c, % -0.29 -0.43 to -0.14 -0.25 -0.40 to -0.11 Weight, kg -2.8 -3.5 to -2.1 -4.4 -5.2 to -3.7 FPG, mg/dL -8.5 -22.5 to 5.5 -11.5 -25.6 to 2.6 TDD, units/d -4.1 -7.9 to -0.3 -7.6 -11.3 to -3.8 Basal, units/d -4.3 -6.2 to -2.4 -5.3 -7.2 to -3.4 Bolus, units/d -0.3 -3.3 to 2.7 -3.2 -6.2 to -0.2 • Proportion adults achieving HbA1c < 7.0%: PBO 5.7%, C100 10.1%, C300 11.2% • Documented hypoglycemia: PBO 96.6%, C100 98.3%, C300 99.1%

o Event rate/pt-yr exposure: PBO 80.6, C100 70.7, C300 79.2 • Pts experiencing SH: PBO 2 (1.7%), C100 3 (2.6%), C300 8 (6.8%)

Safety: Adverse Event Summary

Adverse Event PBO (n = 117)

C100 (n = 117)

C300 (n = 117)

GMI, females/total females (%) (*no GMI reported in males) 3/54 (5.6) 2/48 (4.2) 11/52 (21.2)

UTI, pts (%) 2 (1.7) 5 (4.3) 6 (5.1) Ketone-related events, pts (%)*

DKA requiring hospitalization, n (%) 5 of 12 pts euglycemic

Increased urinary ketones and mild/moderate DKA or acidosis, n (%)

0 (0) 0 (0)

0 (0)

6 (5.1) 5 (4.3)

1 (0.9)

11 (9.4) 7 (6.0)

5 (4.3) *17 pts experienced 18 events

Author’s Conclusion

Canagliflozin reduced HbA1c, weight, and insulin dose; however, increased DKA events, which will require additional mitigation strategies to reduce risk

Critique Strengths: • RCT • % CSII reflective of

general population • Self-titration • Employed insulin dose

adjustment algorithm • Lack of home ketone

monitoring increased real-world validity

Limitations: • Soft primary outcome • Lack clarity on generation of hypoglycemic event rate • 3-page supplementary appendix and no protocol • Low risk DKA population • Unable to determine long-term safety and efficacy • Glucose variability not addressed • Blood pressure not evaluated

Take Home Point(s)

Although canagliflozin improved glycemic control, reduced weight, and decreased insulin dose, DKA number needed to harm (NNH) 14 for ketone-related events and 20 for DKA requiring hospitalization unacceptably high given low-risk population

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Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24-week results from a multicentre, double-blind, phase 3,

randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(11):864-876.57 Objective Assess whether D5 or D10 added to adjustable insulin can safely improve glycemic

control in individuals with T1DM Study Design Phase 3, multicenter, randomized, double-blind, PBO-controlled trial

• Enrolled November 2014 to April 2016 at 43 sites in 17 countries • 8-wk lead-in period to optimize diabetes management • Randomized 1:1:1 to once daily D5, D10, or PBO for 24-wk treatment period

o Stratified by current use of CGM, method of insulin administration (MDI vs. CSII), and baseline HbA1c (≥ 7.5 to < 9.0% vs. ≥ 9.0 to ≤ 10.5%)

o Recommended TDD be reduced symmetrically in basal and bolus insulin by ≤ 20% after first study drug dose and then titrating back towards baseline levels

o Insulin adjusted by providers based on self-monitoring of blood glucose (SMBG) • Provided DKA education and ketone meters; required to monitor if symptomatic • DKA adjudication committee classified DKA events as definite, possible, or unlikely

Population Inclusion: • Men and nonpregnant

women 18 to 75 years old (y.o.)

• Inadequately controlled T1DM, defined as HbA1c of 7.7-11.0% at screening and 7.5-10.5% at randomization

• Prescription insulin ≥ 12 mos prior to enrollment, with TDD ≥ 0.3 units/kg/day for ≥ 3 mos before screening

• C-peptide < 0.7 ng/mL • BMI ≥ 18.5 kg/m2

Exclusion: • Hx of T2DM, maturity onset diabetes of the young, or

diabetes insipidus • Symptoms of poorly controlled diabetes • Prior pancreatic surgery, chronic pancreatitis, or

other pancreatic disorder leading to decreased β-cell capacity

• DKA requiring medical intervention within 1 mo prior to screening

• Hospital admission for hyper- or hypoglycemia within 1-mo pre-screening; frequent SH episodes

• CVD within 6 mos pre-screening, unstable or rapidly progressing renal disease, significant hepatic disease, or malignancy within 5 yrs

• Calculated creatinine clearance < 60 mL/min • Further criteria in supplementary appendix

Outcome(s) Primary: change in baseline HbA1c after 24 wks of treatment Secondary: % change in TDD and bodyweight, change in mean value of 24-hr glucose readings and mean amplitude of glucose excursion (MAGE) of 24-hr CGM readings, % change of 24-hr CGM glucose readings within target range of > 70-180 mg/dL, and proportion with HbA1c decrease of ≥ 0.5% without SH Safety: hypoglycemia, DKA, hepatobiliary events, GMI, UTI, volume depletion, fractures, worsening renal function, hypersensitivity reactions, and CV AEs

Statistical Methods

• Sample size 243 pts/group for ~90% power to detect mean HbA1c difference of 0.35% between each dapagliflozin group and PBO at a 2-sided significance level of 0.0262 with a standard deviation of 1.1%; planned 256/group assuming no post-baseline assessment in 5% of pts

• Efficacy analyses mITT with randomized pts receiving ≥ 1 dose, excluding initial 55 pts due to randomization error; treatment effects through pairwise comparisons o Primary endpoint analyzed with longitudinal repeated-measures analysis o Secondary endpoints only evaluated if primary endpoints significant

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• Safety analysis mITT with all randomized pts receiving ≥ 1 dose Baseline Characteristics

• 1605 enrolled 833 randomized to D5 (n = 277), D10 (n = 296), PBO (n = 260): 758 (91.0%) completed 24-wks

• Groups well-matched – more women in D5 (57%) than D10 (50%) or PBO (49%) o Avg age 42.5 yrs, majority white and from Europe (~1/4 from North America), and

mean baseline BMI was 28.3 kg/m² o Mean duration of diabetes 20.3 yrs, baseline HbA1c 8.53% o Avg baseline TDD of 62.1 units (0.76 units/kg) in D5, 59.4 units (0.71 units/kg) in

D10, and 63.1 units (0.74 units/kg) in PBO o MDI 63% vs. CSII 37%, CGM 33% o ~75% of participants in HbA1c range ≥ 7.5% to 9.0% at randomization

Endpoints Primary: significant HbA1c reduction over 24 wks with both D5 (n = 259) and D10 (n = 259) vs. PBO (n = 260); confirmed by sensitivity analyses • D5 vs. PBO: adjusted mean change -0.42; 95% CI, -0.56 to -0.28; p < 0.0001 • D10 vs. PBO: adjusted mean change -0.45; 95% CI, -0.58 to -0.31; p < 0.0001

Secondary: Secondary Efficacy Outcomes

Endpoint D5 vs. PBO D10 vs. PBO

Mean 24-Wk Difference (95% CI) P Value Mean 24-Wk

Difference (95% CI) P Value

Insulin TDD, % -8.8 (-12.6 to -4.9) < 0.0001 -13.2

(-16.8 to -9.4) < 0.0001

Insulin TDD/kg, %

-5.5 (-9.2 to -1.6) 0.0064 -9.8

(-13.4 to -6.1) < 0.0001

Weight, % -2.96 (-3.63 to -2.28) < 0.0001 -3.72

(-4.38 to -3.05) < 0.0001

CGM Mean Value, mg/dL

-15.3 (-20.2 to -10.5) < 0.0001 -18.0

(-23.0 to -13.1) < 0.0001

CGM MAGE, mg/dL

-17.3 (-22.5 to -12.1) < 0.0001 -18.9

(-24.1 to -13.7) < 0.0001

24-hr CGM at goal of > 70-180 mg/dL, %

9.1 (6.8 to 11.4) < 0.0001 10.7

(8.4 to 12.9) < 0.0001

• Reductions in TDD proportional for basal and bolus insulin requirements o D5: adjusted mean change from baseline -11.6% (basal), -14.3% (bolus) o D10: adjusted mean change from baseline -13.7% (basal), -18.0% (bolus) o PBO: adjusted mean change baseline -0.6% (basal), -4.6% (bolus)

• HbA1c reduction ≥ 0.5% without SH significant for both groups o D5 vs. PBO: odds ratio (OR), 3.09; 95% CI, 2.10 to 4.56; p < 0.0001 o D10 vs. PBO: OR, 3.29; 95% CI, 2.23 to 4.85; p < 0.0001

Safety: Adverse Event Summary

Adverse Event D5 (n = 277) D10 (n = 296) PBO (n = 260) GMI, pts (%) 34 (12) 33 (11) 7 (3) UTI, pts (%) 19 (7) 11 (4) 13 (5) Renal worsening/failure, pts (%) 4 (1) 2 (1) 0 (0) Fractures, pts (%) 4 (1) 3 (1) 3 (1)

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Hypoglycemia Documented, pts (%) SH, pts (%) SH, events (%) SH, events/100 pt-yrs

220 (79)

21 (8) 31 (1) 25.2

235 (79)

19 (6) 39 (1) 29.5

207 (80)

19 (7) 54 (1) 47.8

DKA Definite, pts (%)

Euglycemic DKA, events Possible, pts (%) Unlikely, pts (%)

4 (1)

0 5 (2) 8 (3)

5 (2)

2 7 (2) 8 (3)

3 (1)

0 1 (< 1) 3 (1)

Author’s Conclusion

As the first oral adjunct to insulin for T1DM to show HbA1c and weight loss benefit, along with reduced hypoglycemia risk, compared with insulin alone, concomitant dapagliflozin represents a promising addition to insulin therapy

Critique Strengths: • Large RCT • Glucose variability • No insulin adjustment

algorithm more closely reflects clinical practice

• DKA adjudicated by blinded committee

• Evaluated many AEs

Limitations: • Generalizability • Lack of long-term efficacy and safety data • Excluded pts with common comorbidities • Insulin adjustment done solely by investigator • No set criteria to define possible or unlikely DKA • Outcome bias • Blood pressure not evaluated

Take Home Point(s)

Potential T1DM FDA indication for dapagliflozin based on findings; however, when possible DKA added to definitive events, less favorable profile revealed (NNH 47)

Garg SK, Henry RR, Banks P, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N

Engl J Med. 2017;377(24):2337-2348.51 Objective Determine safety and efficacy of sotagliflozin as adjunct to insulin in T1DM Study Design Phase 3, multicenter, randomized, double-blind, PBO-controlled trial

• October 2015 to April 2017 at 133 sites across 19 countries • Randomized 1:1 to once daily PBO or S400 prior to first meal of day for 24 wks • Continued approved insulin regimen with exception of receiving 30% lower bolus

insulin dose with first meal of study period • Insulin adjusted by providers based on SMBG using algorithms targeting ADA goals • Lab HbA1c, fasting plasma, and urinary glucose levels masked after randomization • Wk 16 to 24, investigators informed of HbA1c > 11.0% to make necessary changes • Pts provided information/supplies for detection of ketosis (urine ketone strips, β-

hydroxybutyrate meter and strips), urogenital hygiene, and proper hydration Population Inclusion:

• Men and nonpregnant women ≥ 18 y.o. with T1DM for ≥ 1 yr

• Stable basal insulin dose ≥ 2 wks prior to screening visit

• HbA1c 7.0-11.0% • BMI ≥ 18.5 kg/m2

Exclusion: • SH within 1 mo prior to screening • DKA within 1 mo or ≥ 2 events within 6 mos • T2DM or severely uncontrolled T1DM • eGFR < 45 m/min/1.73 m2 • Chronic corticosteroids within 6 mos of screening • β-hydroxybutyrate > 0.6 mmol/L at screening • Severely immunocompromised • Pancreatitis within 12 mos of screening

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• Able and willing to perform SMBG

• Adequate contraception by women

• Hepatitis or lab-confirmed abnormal liver function • NYHA class III-IV • CVD within 3 mos of screening • Further criteria in supplementary appendix

Outcome(s) Primary: HbA1c < 7.0% with no episodes of SH or DKA Secondary: change from baseline sotagliflozin vs. PBO in HbA1c, weight, mean daily bolus insulin dose, and systolic blood pressure (SBP) in pts with SBP ≥ 130 mmHg Other: HbA1c < 7.0% with no weight gain, DKA, number of documented hypoglycemic events, SH, change from baseline in diastolic blood pressure (DBP), FPG, mean daily basal insulin dose, mean daily total insulin, and eGFR

Statistical Methods

• mITT with pts who underwent randomization and received ≥ 1 dose • Sample size 700 pts/group to provide ~90% power to detect effect size of 0.10 for

primary endpoint, assuming 50% of pts would achieve endpoint • 2-sided α of 0.05 for primary and secondary efficacy variables • Sensitivity analysis performed to account for missing data • Categorical variables analyzed as proportions and results summarized as % points • Safety analysis descriptive

Baseline Characteristics

• 1755 screened 1405 randomized 1402 received dose of S400 (n = 699) or PBO (n = 703): 1229 (87.7%) completed 24-wks

• Groups well-matched o Avg age 43.3 y.o. S400 vs. 42.4 y.o. PBO, female 48.8% S400 vs. 51.8% PBO, white

88.6% S400 vs. 88.3% PBO, and mean BMI 28.3 kg/m2 S400 vs. 28.1 kg/m2 PBO o Mean duration of diabetes 20.5 yrs S400 vs. 19.6 yrs PBO, baseline HbA1c 8.3%

S400 vs. 8.2% PBO, FPG 165.1 mg/dL S400 vs. 163.4 mg/dL PBO o Mean TDD 56.9 units/d (0.69 units/kg) S400 vs. 58.4 units/d (0.71 units/kg) PBO o MDI 60.7% S400 vs. 60.2% PBO o Avg SBP 122.0 mmHg S400 vs. 121.8 mmHg PBO, DBP 76.4 mmHg S400 vs. 76.7

mmHg PBO, SBP ≥ 130 mmHg 29.0% S400 vs. 28.9% PBO Endpoints Primary:

Significant Primary Efficacy Endpoints

Endpoint S400

(n = 699) PBO

(n = 703) Difference (95% CI) P Value

pts (%) % points HbA1c < 7.0% and no SH or DKA

All pts CSII pts MDI pts

200 (28.6) 88 (32.0)

112 (26.4)

107 (15.2) 45 (16.1) 62 (14.7)

13.4 (9.0 to 17.8) 15.9 (8.6 to 23.3) 11.8 (6.1 to17.4)

< 0.001 < 0.001 < 0.001

HbA1c ≥ 7.0% and ≥ 1 DKA episode 18 (2.6) 4 (0.6) 2.0 (0.7-3.3) 0.003

Secondary: Efficacy Endpoints

Endpoint S400 (n = 699)

PBO (n = 703)

LS Mean Difference from PBO

HbA1c, % (95% CI) P Value

-0.79 (-0.85 to -0.73)

< 0.001

-0.33 (-0.39 to -0.27)

< 0.001

-0.46 (-0.54 to -0.38)

< 0.001

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Weight, kg (95% CI) P Value

-2.21 (-2.45 to -1.97)

< 0.001

0.77 (0.53 to 1.01)

< 0.001

-2.98 (-3.31 to -2.66)

< 0.001 SBP in pts with SBP ≥ 130 mmHg, mmHg (95% CI) P Value

-9.2 (-11.0 to -7.4)

< 0.001

-5.7 (-7.5 to -3.9)

< 0.001

-3.5 (-5.7 to -1.3)

0.002 Daily bolus insulin dose, units/d (95% CI) P Value

-3.93 (-4.85 to -3.01)

< 0.001

-1.09 (-2.00 to -0.17)

0.020

-2.84 (-4.05 to -1.64)

< 0.001 Other: • HbA1c < 7.0% with no weight gain: 171/699 (24.5%) S400 vs. 51/703 (7.3%) PBO • S400 LS mean difference from PBO

o FPG: -23.2 mg/dL; 95% CI (-30.4 to -16.0); P < 0.001 o TDD: -5.25 units/day; 95% CI (-6.67 to -3.83); P < 0.001 o Daily basal insulin dose: -2.60 units/day; 95% CI (-3.39 to -1.81); P < 0.001 o DBP, mITT population: -1.3 mmHg; 95% CI (-2.1 to -0.6); P < 0.001 o eGFR: -0.24 mL/min/1.73 m2; 95% CI (-1.52 to 1.04); P = 0.71

Adverse Event Summary Adverse Event S400 (n = 699) PBO (n = 703) GMI, pts (%) 45 (6.4) 15 (2.1) UTI, pts (%) 25 (3.6) 27 (3.8) Diarrhea, pts (%) 29 (4.1) 16 (2.3) Fractures, pts (%) 4 (0.6) 5 (0.7) Hypoglycemia

Documented hypoglycemia, pts (%) ≤ 55 mg/dL, pts (%) SH, pts (%)

CSII, pts (%) MDI, pts (%)

673 (96.3) 528 (75.5)

21 (3.0) 10 (3.6) 11 (2.6)

670 (95.3) 559 (79.5)

17 (2.4) 5 (1.8)

12 (2.8) Serious and nonserious acidosis-related adverse events, pts (%)

DKA, pts (%) CSII, pts (%) MDI, pts (%)

60 (8.6) 21 (3.0) 12 (4.4) 9 (2.1)

17 (2.4) 4 (0.6) 2 (0.7) 2 (0.5)

Author’s Conclusion

Significantly larger proportion of adults in S400 group achieved primary endpoint; however, DKA rate significantly higher in S400 pts not meeting HbA1c < 7.0%

Critique Strengths: • Large RCT • Employed insulin dose adjustment

algorithms • Included DKA results by

administration method • Pts with CV comorbidities • Evaluated blood pressure • Independent agencies involved

Limitations: • Masking HbA1c favored active intervention • Infrequent participant-provider visits • Low risk DKA population • Lack of long-term efficacy and safety data • Glucose variability not addressed

Take Home Point(s)

Increased DKA risk (NNH 42), especially in CSII users (NNH 27), in relatively low risk population potentially offsets benefits of sotagliflozin

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Table 8: Recent Trial Results

Author Findings Buse et al.58 Sep 2018

inTandem1 study: 52-wk, phase 3, multicenter, double-blind, PBO-controlled trial, randomized North American adults with T1DM to once daily PBO (n = 268), sotagliflozin 200 mg (S200) (n = 263), and S400 (n = 262) post 6-wk insulin optimization period • Significant efficacy outcomes o PBO-adjusted HbA1c reduction 24 wks: 0.36% S200, 0.41% S400 (P < 0.001) o PBO-adjusted HbA1c reduction 52 wks: 0.25% S200, 0.31% S400 (P < 0.001) o PBO-adjusted mean SBP reduction 12 wks: 3.5 mmHg S200, 4.2 mmHg S400 (P < 0.001) o Mean treatment differences vs. PBO 52 wks FBG: S200 12.2 mg/dL lower (P = 0.028), S400 19.4 mg/dL lower (P < 0.001) Bolus dose: S400 15.6% lower; basal dose: S400 11.9% lower (P < 0.001) Time in range: S400 increased 10.4% (P < 0.001) relative to PBO Weight: S200 3.1 kg lower (P < 0.001), S400 4.3 kg lower (P < 0.001)

• Notable safety outcomes o SH: 26 pts (9.7%) PBO, 17 pts (6.5%) S200, 17 pts (6.5%) S400 o DKA: 1 pt (0.4%) PBO, 9 pts (3.4%) S200, 11 pts (4.2%) S400; 7 episodes euglycemic CSII: 1/160 pts (0.6%) PBO, 8/156 pts (5.1%) S200, 7/157 pts (4.5%) S400 MDI: 0 pts (0%) PBO, 1/107 pts (0.9%) S200, 4/105 pts (3.8%) S400

• Conclusion: sotagliflozin with optimized insulin associated with improved clinical outcomes (i.e., sustained HbA1c reduction, weight loss, lower insulin dose, longer time in range, and fewer episodes of SH), but more cases of DKA

Danne et al.59 Sep 2018

inTandem2 study: 52-wk, phase 3, multicenter, double-blind, PBO-controlled trial, randomized European (and Israeli) adults with T1DM to once daily PBO (n = 258), S200 (n = 261), and S400 (n = 263) post 6-wk insulin optimization period • Significant efficacy outcomes o PBO-adjusted HbA1c reduction 24 wks: 0.37% S200, 0.35% S400 (P < 0.001) o PBO-adjusted HbA1c reduction 52 wks: 0.21% S200, 0.32% S400 (P < 0.001) o Mean treatment differences vs. PBO 24 wks FBG: S200 21.6 mg/dL lower, S400 25.6 mg/dL lower (P < 0.001) Time in range: S200 increased 8.4% (P = 0.044), S400 increased 13.4% (P < 0.001) 2-hr PG: S200 50.4 mg/dL lower (P = 0.009), S400 75.6 mg/dL lower (P < 0.001) Bolus insulin dose: S200 12.9% lower (P < 0.001), S400 16.4% lower (P < 0.001) Basal insulin dose: S200 5.8% lower (P = 0.007), S400 4.7% lower (P = 0.03)

o Mean treatment differences vs. PBO 52 wks FBG: S400 15.7 mg/dL lower (P < 0.008) Weight: S200 2.18 kg lower (P < 0.001), S400 2.92 kg lower (P < 0.001)

o PBO-adjusted mean SBP reduction 12 wks: S400 2.8 mmHg lower (P = 0.001) • Notable safety outcomes o SH: 13 pts (5.0%) PBO, 13 pts (5.0%) S200, 6 pts (2.3%) S400 o DKA: 0 pts (0%) PBO, 6 pts (2.3%) S200, 9 pts (3.4%) S400 CSII: 0 pts (0%) PBO, 1/68 pts (1.5%) S200, 5/67 pts (7.5%) S400 MDI: 0 pts (0%) PBO, 5/193 pts (2.6%) S200, 4/196 pts (2.0%) S400

o Acidosis-related adverse events Any: 3 (1.2%) PBO, 23 (8.8%) S200, 30 (11.4%) S400 Serious: 0 (0%) PBO, 7 (2.7%) S200, 13 (4.9%) S400

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• Conclusion: sotagliflozin with optimized insulin associated with significant HbA1c reductions, but more DKA episodes

Mathieu et al.60 Sep 2018

DEPICT-2 study: 24-wk, phase 3, multicenter, double-blind, PBO-controlled trial, randomized adults with T1DM and inadequate glycemic control to once daily PBO (n = 272), D5 (n = 271), and D10 (n = 270) • Significant efficacy outcomes o PBO-adjusted HbA1c reduction: 0.37% D5, 0.42% D10 (P < 0.0001) o PBO-adjusted mean TDD % reduction: 10.8% D5, 11.1% D10 (P < 0.0001) o Adjusted mean basal insulin change: 1.5% PBO, -11.2% D5, -16.7% D10 o Adjusted mean bolus insulin change: -2.59% PBO, -11.6% D5, -8.3% D10 o PBO-adjusted weight reduction: 3.2% D5, 3.7% D10 (P < 0.0001) o Mean treatment differences vs. PBO 24-hr CGM mean value: -15.7 mg/dL D5, -19.7 mg/dL D10 (P < 0.0001) 24-hr CGM in target range: 9.0% D5, 10.7% D10 (P < 0.0001)

• Notable safety outcomes o SH: 7.7% PBO, 6.3% D5, 8.5% D10 o DKA: 0 pts (0%) PBO, 7 pts (2.6%) D5, 6 pts (2.2%) D10; 3 episodes euglycemic CSII: 0 pts (0%) PBO, 6 pts (6.5%) D5, 3 pts (3.3%) D10

• Conclusion: dapagliflozin associated with significant reduction in HbA1c, mean glucose, glycemic variability, time in glycemic target range, weight, and TDD, but more DKA events

Recommendations

1. SGLT inhibitor summary A. Enhanced glycemic control B. Decreased TDD C. Reduced weight D. Improved BP (particularly SBP) E. Commonly associated AEs as expected F. Similar hypoglycemia, including SH events G. Increased risk of DKA, particularly with CSII H. No long-term CV or renal outcomes

2. Recommendation A. Consider dapagliflozin or sotagliflozin in inadequately controlled T1DM as adjunct to

insulin in adherent, non-elderly adults preferably on MDI with high health literacy, willing to undergo extensive education and perform home ketone monitoring

B. Caution with adults using CSII C. Alternatively, could initiate if inadequate glycemic control and adult unwilling to titrate

insulin secondary to weight concerns D. Reduce TDD by no more than 20% at time of initiation and titrate, as necessary E. Avoid if age < 18 y.o. or ≥ 65 y.o.; BMI < 18.5 kg/m2; hx of DKA, GMI, or UTI; serious CV,

renal, or hepatic comorbidities; hx of pancreatitis or pancreatectomy; and initiating for sole purpose of CV or renal benefit

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